This invention relates to a process for the preparation of (S)(+)-4,4'-(1-methyl-1,2-ethanediyl)bis-(2,6-piperazinedione), which is useful as an active ingredient in a pharmaceutical composition to spare cardiotoxicity of other pharmaceuticals useful for aiding regression and palliation of cancer in mammals.
The usefulness of the above 2,6-piperazinedione is disclosed in U.S. Pat. No. 3,941,790 to Creighton, which also discloses a method in Example 3 of preparing the desired 2,6-piperazinedione by treating d-1,2-diaminopropane tetraacetic acid monohydrate with formamide. The method results in a modest 43% yield before crystallization, and requires vacuum distillation of a high boiling solvent, formamide, to isolate the product. Alternate synthesis methods for other bis-diketopiperazines are described, but when applied to the synthesis of the desired 2,6-piperazinedione of the present invention, yields similar to those of Example 3 were obtained.
In the Journal of Medicinal Chemistry, Vol. 20, No. 5, pages 630-635 (1977), and in the Journal of Medicinal Chemistry, Vol. 21, No. 12, pages 1194-1197 (1978), Witiak, et. al., describe methods for the preparation of cis- and trans-cyclopropyl-bis-2,6(piperazinediones). The method involves a synthesis of amidoesters of the formula ##STR1## from the corresponding tetramethyl esters of the formula ##STR2## by treating the tetramethyl esters with ammonia or sodium hydride and formamide. The amidoesters were not isolated, but were converted in poor yield into the corresponding 2,6-piperazinediones by treatment with a strong base, such as sodium methoxide or sodium hydride.
Although the prior art processes provide the desired 2,6-piperazinediones, the present invention results in a much higher yield of the desired 2,6-piperazinediones than the previously available methods. In addition, the present invention does not require distillation of a high boiling solvent, such as formamide, which greatly facilitates production of multi-kilogram quantities of the desired product.